title: Gonadotropin-releasing hormone-regulated prohibitin mediates apoptosis of the gonadotrope cells.
abstract: GnRH regulates circulating levels of the gonadotropins but has also been implicated in establishing the gonadotrope cell population. Consistent with this, GnRH induces proliferation of partially differentiated gonadotropes, while reducing the numbers of fully differentiated cells. We have previously reported that the proapoptotic protein, prohibitin (PHB) is expressed more abundantly in gonadotrope-derived LβT2 cells than in partially differentiated αT3-1 gonadotrope precursor cells, suggesting a possible role for PHB in GnRH-induced apoptosis. We show here that PHB is required for GnRH-induced apoptosis in mature gonadotropes. PHB expression and activity are regulated by GnRH: its transcription is via c-Jun NH2-terminal kinase, whereas its nuclear export follows activation of ERK. Moreover, PHB levels are down-regulated by microRNA27, which is expressed at lower levels in mature gonadotropes, possibly explaining the switch to an apoptotic response with development. PHB is required for mitochondrial import of the proapoptotic BAX, whose expression is also induced by GnRH-activated c-Jun NH2-terminal kinase, as is expression of the BH3-only protein, HRK, and this too plays a role in GnRH-induced apoptosis. Finally, we show that gonadotrope-specific PHB-knockout mice display reproductive abnormalities, including a larger gonadotrope population, increased LH levels, reduced fertility, and altered gonad development. We thus demonstrate a role for PHB in GnRH-induced cell death in mature gonadotropes, which is crucial for the normal development and function of the reproductive axis.
authors.affiliation: Faculty of Biology, Technion-Israel Institute of Technology, Haifa, 32000 Israel. philippa@tx.technion.ac.il.
authors.forename: Dana
authors.initials: D
authors.lastname: Savulescu
authors.forename: Jiajun
authors.initials: J
authors.lastname: Feng
authors.forename: Yueh Shyang
authors.initials: YS
authors.lastname: Ping
authors.forename: Oliver
authors.initials: O
authors.lastname: Mai
authors.forename: Ulrich
authors.initials: U
authors.lastname: Boehm
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Philippa
authors.initials: P
authors.lastname: Melamed
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D052681:Gonadotrophs / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology*; D007246:Infertility / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D009479:Neuropeptides / Q000378:metabolism; D010053:Ovary / Q000473:pathology; D000091402:Prohibitins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D013737:Testis / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494827:Bax protein, mouse; C107631:Hrk protein, mouse; D035683:MicroRNAs; C540674:Mirn27 microRNA, mouse; D009479:Neuropeptides; D000091402:Prohibitins; D012097:Repressor Proteins; D051028:bcl-2-Associated X Protein; D007987:Gonadotropin-Releasing Hormone; D048049:Extracellular Signal-Regulated MAP Kinases